Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

Abstract

This “Controversies in Cardiovascular Research” article evaluates the evidence for and against the hypothesis that the circulating blood level of Growth Differentiation Factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by a number of independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member GDF8 actually impairs skeletal muscle repair in old animals. One possible explanation for what appears to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age dependent changes in GDF11 are still not well known. The more important issue is if increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.

Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease

“…An additional contributor to the inconsistent conclusions about GDF11’s role in aging may be the experimental contexts (e.g., species, models, doses of recombinant protein) in which it has been studied. These issues have been discussed exhaustively elsewhere (Egerman et al, 2015; Harper et al, 2016; McNally, 2016; Walker et al, 2016). …”

Supraphysiological levels of GDF 11 induce striated muscle atrophy

“…Given the recent controversy surrounding GDF11 as an anti‐aging therapy (Harper et al , ; Walker et al , ), it is clear that additional mechanistic studies on this TGFβ superfamily member are required. While the physiological role of endogenous GDF11 in postnatal striated muscle remains ambiguous, the biomedical importance of this ligand is exemplified by the recent demonstration that elevated GDF11 levels associate with patient frailty and problematic recovery following cardiovascular disease (CVD) intervention (Schafer et al , ).…”

Disease drivers of aging

“…New discoveries have begun to shed light on this issue, which include several studies challenging GDF11's antiaging, progrowth influence (reviewed in Refs. and ). A critical emerging experimental consideration is the requirement of detection methods that are able to resolve GDF11 from MSTN.…”

“…The realization that these assays were insufficiently discerning has underscored the need for new detection methods (reviewed in Ref. ). The most robust approaches are anticipated to leverage mass spectrometry (MS) for quantification of GDF11‐ and MSTN‐based amino sequence differences.…”